Investigation has heretofore been made on injections that provide the sustained release of a water-soluble drug for a long time, most of which comprise poly-lactic-co-glycolic acid (PLGA) as a base (see e.g., Japanese Patent Laid-Open Nos. 11-286403, 2000-239104, and 2002-326960). Alternatively, sustained-release microcapsules that contain a human growth hormone (hGH) and comprise PLGA as a base have been reported (see e.g., Nature Medicine, 2: 795-799, 1996). Sustained-release microcapsules that contain leuprorelin, a LHRH agonist, and comprise PLGA as a base have also been reported (see e.g., Chemical Pharmaceutical Bulletin, 36: 1095-1103, 1988). PLGA is a biodegradable base that hydrolyzes and eliminates in the living body, and this property is preferable for a base of an injection.
Although an organic solvent that dissolves PLGA is generally used for producing a sustained-release preparation with PLGA, hGH is denatured in the organic solvent and a portion thereof is inactivated. Such reduction in activity not only impairs efficacy but poses the risk of adversely affecting a living body. Furthermore, hGH is highly soluble in water, and the use of a PLGA preparation inevitably results in the excessive release of hGH in the early stage after administration. In addition, although the use of hydrogel or the like has been reported, the hydrogel is difficult to administer by means of a typical injection. That is, a thick needle that permits the gel to pass therethrough must be used and is unfavorable for patients. Sustained-release particles using hydroxyapatite and a human growth hormone that is a bioactive drug have already been reported (see e.g., H. Gautier et al., Journal of Biomedical Material Research, 40,606-613,1998; and J. Guicheux et al., Journal of Biomedical Material Research, 34, 165-170, 1997). However, any of the sustained-release particles are two-component systems where apatite has a large particle size of 40 to 80 μm or 200 μm and is therefore difficult to inject. Moreover, their in vivo sustained-release effect is unknown. Besides, the amount of hGH adsorbed into the apatite particle (the amount of hGH encapsulated) was as low as 1% or less.
For a sustained-release preparation of hGH, a material having so-called biodegradability or a property of eliminating in the living body, which eliminates from a living body about the end of the release of a drug after administration, must be selected as a sustained-release base. In its production, a sustained-release preparation is prepared with the use of an organic solvent avoided as much as possible for preventing the denaturation of hGH. At the same time, the initial burst release (the release of an excessive drug in the early stage after administration) of hGH must be small. Moreover, the amount of a drug encapsulated in a microparticle preparation is brought to 10% or more by weight. The preparation capable of being easily administered with a thin injection needle must be prepared, wherein the duration of the sustained-release of a drug extends at least 3 days or more.
The present inventors have found that the use of fine particles of a porous apatite derivative for solving these problems achieves a preparation combining biodegradability with sustained-release performance, without the use of an organic solvent. The present inventors have further found that the use of hGH in combination with a water-soluble divalent metal compound achieves the sustained-release of hGH over at least 3 days or more and reduces initial burst release. In addition, the present inventors have found that a hGH content of 10% or more can be attained and hGH up to 20% can quantitatively be adsorbed and contained, and also found that the obtained fine granular preparation has excellent dispersion and needle penetration properties and easily passes through a 27 G injection needle.
Thus, an object of the present invention is to provide a sustained-release fine granular preparation of a human growth hormone which combines biodegradability with sustained-release performance while avoiding the use of an organic solvent as much as possible, allows the sustained release of a human growth hormone over 3 days or more and reduction in the initial burst release, can contain a human growth hormone at 10% or more, can quantitatively adsorb and include a human growth hormone at up to 20%, and has excellent dispersion and needle penetration properties. The present invention is also intended to provide a process for producing the sustained-release fine granular preparation of a human growth hormone.